Cardiovascular diseases are caused by a number of synergistic factors of which elevated levels of cholesterol and triglycerides (triacylglycerol) in the blood are considered the most important. Cholesterol is an important building block for human and animal cells since is it one of the constituents of cellular membranes. The human cell is capable of synthesizing cholesterol, but cholesterol is also taken up from food sources. Both processes play an important role in cholesterol metabolism in humans.
Besides its essential function as building block of cellular membranes, cholesterol also plays a negative role in the occurrence of cardiovascular diseases (such as heart attack, seizure, and peripheral vascular diseases), in particular in relation to the occurrence of hardening of blood vessel walls (atherosclerosis). An elevated level of cholesterol especially in combination with elevated levels of triglycerides in the blood is the most important predictive (risk) factor for the occurrence of cardiovascular diseases and atherosclerosis.
In the blood cholesterol is transported in lipoproteins, which can be distinguished in a number of classes based on size and density. The very-low-density lipoproteins (VLDL), the intermediate-density lipoproteins (IDL), the low-density lipoproteins (LDL) and the high-density lipoproteins (HDL) being the most important.
Experimental and clinical research has shown that especially the amount of cholesterol transported by the VLDL, the IDL and the LDL form a risk factor for the occurrence of cardiovascular disease (the pro-atherogenic cholesterol). The HDL provides a protective effect on the occurrence of cardiovascular disease.
Randomized prospective clinical studies have shown that reduction of the plasma cholesterol and triglyceride level has a beneficial effect on the incidence of cardiovascular diseases and on the mortality as a result of these diseases. A provision is that this reduction is the result of a reduction in the pro-atherogenic cholesterol in VLDL, IDL and/or LDL. In order to treat and prevent cardiovascular disease in humans it is desired to reduce the level of the pro-atherogenic cholesterol, and to absolutely or relatively increase the proportion of the anti-atherogenic HDL.
In order to prevent and treat vascular and coronary disease in humans it is desired to lower LDL, and to increase the relative or absolute contribution of HDL.
In practice there are several possibilities to attain the desired reduction in plasma cholesterol. The main options being:
a. inhibition of cholesterol synthesis;
b. increasing the rate of cholesterol disposal (or its conversion products, primarily bile acids); and
c. reducing the intake (absorption) of cholesterol and bile acids from the intestine.
Drugs that are currently applied for the inhibition of cholesterol synthesis or for the treatment of hypercholesterolemia target the enzyme hydroxymethyl-glutaryl-coenzyme A reductase (HMG-CoA reductase) the enzyme catalyzing the rate-limiting step in hepatic cholesterol synthesis. These HMG-CoA reductase inhibitors (or statins) are generally synthetic compounds that block the activity of the enzyme. Examples are simvastatin (“Zocor®”), pravastatin (“Pravachol®”) and atorvastatin (“Lipitor®”).
In order to increase the rate of cholesterol disposal bile acid-absorbing resins (e.g. cholestyramine, “Questran®”) may be used. By the absorption of bile acids to these resins the secretion of bile acids in the feces increases and the resorption of bile acids from the intestinal lumen to the blood decreases which results in a shortage of bile acids in the body. This shortage is compensated by the body by an increased conversion of cholesterol into bile acids by the liver. In this way, cholesterol is disposed from the body in the form of bile acid.
Since the absorption of cholesterol from the intestinal lumen is in fact only possible when the cholesterol is kept in soluble form (suspension, solution, dispersion) in the lumen by, amongst others, bile acid, a reduction in the bile acid concentration in the intestine also results in a decreased absorption of cholesterol.
Medicaments that inhibit the (active) absorption of cholesterol from the intestinal lumen by inhibiting the cellular transport systems for cholesterol (and optionally other sterols) as present in the intestinal epithelium are largely in the developmental stage. One of those medicaments (Ezetimibe®) has recently become available in several countries, others are only used experimentally in the clinic.
Besides using medicaments, the above three goals may also be achieved by using other naturally occurring agents or agents derived from naturally occurring products (cf Hassel. 1998. Curr. Opin. Lipidol. 9:7-10). An example of a naturally occurring statin-containing preparation is the so-called red rice, a rice variety that carries a mould that naturally produces the metabolite lovastatin. This metabolite is similar to the cholesterol synthesis-inhibiting medicament lovastatin. Further, use may be made of for instance sterols that occur in plants, i.e. so-called phytosterols, to inhibit the uptake of bile acid and cholesterol from the intestine. This type of compounds now finds practical application in margarine products sold in the Netherlands under the brand names of “Benecol®” or “Becel Pro-actif®”.
Despite the availability of the above agents, medicaments and compounds, there still exists a need for cholesterol lowering agents, in particular for use in the food industry, and preferably for human food products.
Besides lowering plasma cholesterol, lowering plasma triglyceride will also result in lower risk for cardiovascular diseases. Plasma triglyceride reductions can be achieved by administration of, for instance, Niacin which inhibits transport of fatty acids from adipose tissue to the liver for triglyceride synthesis and secretion into the circulation. Fibrates, such as Fenofibrate® and Bezofibrate®, also lead to lower plasma triglyceride levels. These drugs act via enhancement of the oxidation of fatty acids, thereby preventing the synthesis of triglycerides.